Matrix metalloproteinases (MMPs) are endopeptidases that can degrade macro biomolecules, such as collagen, proteoglycan and gelatin, and are grouped into collagenases, gelatinases, stromelysins and membrane-type MMPs. All the MMPs are expressed in the form of a pro-enzyme, and a portion of MMP is cleaved so that MMP is activated (Bond, J. S., et al., Int. J. Biochem., 75, 565-574(1985); Chen, J. M., Chen, W. T., Cell, 48, 193-203(1987); Harris, E. D. et al., Coll Rel Res, 4, 493-512(1984)).
It has been reported that collagenases act on triple-helix form epileptic collagen and gelatin, are grouped into three kinds of collagenases, such as fibroblast collagenase, neutrophil collagenase and collagenase-3, and cleave types I, II and III collagen fibrils (Goldberg, G. I., et al, J. Biol. Chem., 261, 6600-6605(1986); Fini, M. E., et al., Biochemistry, 26, 6155-6165(1987)). In addition, it has been known that these three kinds of collagenases have about 50% or more sequence identity with respect to each other (Borkakoti, et al., Nature Struct. Biol., 1, 106-110(1994); EMBO, J., 13, 1263-1269(1994)).
The structure of the MMPs is divided into three domains: a pro-peptide domain, a catalytic domain and a C-terminal domain. After all of the MMPs are generated and secreted in an inactive, latent form, 80 amino acids of the pro-peptide domain from the N-terminal are cleaved, and MMPs are activated through the removal of the cysteine in the PRCGVPD-sequence motif is (Van Wart, H. E. et al., Proc. Natl. Acad. Sci. USA, 87, 5578-5582(1990)). It has been known that the activity of the activated MMPs is inhibited by coupling with MMP tissue inhibitor of matrix metalloproteinase (TIMP), which is a natural inhibitor, and this coupling is regulated by the catalytic domain (Murphy, et al., J. Niol. Chem., 267, 9612-9618(1992)). Various types of MMPs have substrate specificity, and are expressed in metabolic processes even in normal cells when extracellular matrixes or other collagen structures need to be degraded. Examples of the disease mediated by MMPs include arteriosclerosis, inflammatory disease of the central nervous system, Alzheimer's disease, skin aging, rheumatoid arthritis, osteoarthritis, corneal ulcers, bone disease, proteinuria, abdominal aneurysm disease, degenerative cartilage loss caused by traumatic joint injury, demyelinating disease of the nervous system, cirrhosis, glomerulopathy, premature rupture of the embryonic membrane, inflammatory bowel disease, periodontal disease, macular degeneration associated with age, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, keratoconus, Sjogren's syndrome, myopia, ocular tumor, corneal transplant rejection, angiogenesis, cancer invasion and metastasis, and the like. Rheumatoid arthritis and osteoarthritis are caused by autoimmune disorder, but as the diseases progress, the extracellular matrix of articular cartilage is destroyed. Stromelysins have been recognized as major enzymes in the arthritis and joint trauma, and have been found to play an important role in the conversion of procollagenase into activated collagenase. Therefore, the progression of arthritis can be prevented by inhibiting MMP activity, and it has been reported that MMPs are derived from penetrating leukocytes, fibroblast cells, or external microorganisms.
In addition, the collagenase secreted from the stimulation of inflammatory mediators and the collagenase secreted from bacteria degrade collagen, which is the matrix of periodontal tissues, causing receding gums, which is gradually advanced to cause periodontal diseases. The activities of fibroblast collagenase and stromelysin isolated from gums causing inflammation were verified, and the correlation between the enzyme level and the observed level of gingivitis was confirmed (Overall, C. M. et al., J. Periodontal Res. 22, 81-88(1987)).
MMPs are involved in the pathogenesis of several diseases of the central nerve system (CNS). It is presumed that MMPs destroy myelin or blood-brain barrier (BBB) by allowing inflammatory mononuclear cells to flow into central nerves, and are involved in the accumulation of amyloid beta protein in Alzheimer's disease (Yong, V W, et al., Trends Neurosci 21(2), 75-80(1998)). In addition, it has been reported that: the concentration of MMPs is higher in brains of Alzheimer's disease patients rather than normal brains (Leake A, Morris C M, & Whateley J. Neurosci Lett 291(3), 201-3(2000); the level of gelatinase B in the cerebrospinal fluid is associated with multiple sclerosis and other neurological diseases (Miyazaki, K, et al., Nature 362, 839˜841(1993)); and MMPs also contribute to the degradation and accumulation of amyloid beta protein (Backstrom J R, et al., J neurosci 16(24), 7910-9(1996)).
Since MMPs induce skin aging, the relief and prevention of wrinkles can be expected through the inhibition of MMPs, and MMPs promote angiogenesis and cancer invasion and metastasis through the degradation of basement membranes. Therefore, MMPs play a very important role in cancer invasion and metastasis through the degradation of basement membranes and also mediate various diseases, and thus the development of medicines capable of inhibiting MMPs is required. However, these inhibitors can be used as ideal therapeutics when the inhibitors can be safely used during a long period of time, so that the development of less toxic preparations as MMP activity inhibitors is required. For effective treatment of various diseases mediated by MMPs, MMP inhibitors are being actively studied, and the development of MMP inhibitors is effectively employed for the treatment of various diseases.
Throughout the entire specification, many papers and patent documents are referenced and their citations are represented. The disclosure of the cited papers and patent documents are entirely incorporated by reference into the present specification, and the level of the technical field within which the present invention falls and the details of the present invention are explained more clearly.